Lactoferrin (LF) is a metal binding glycoprotein of M.sub.r 77,000 found in milk, tears, saliva, bronchial, intestinal, vaginal and other secretions. LF is also present in the secondary granules of neutrophils. Lactoferrin plays an important role in numerous inflammatory and immune response functions such as regulation of monocyte colony stimulating factor synthesis, regulation of interleukin synthesis, activation of natural killer cell activity, inhibition of metastasis, and maturation of T-cells.
The amino acid sequence of LF has been determined by protein-sequencing and sequencing of cDNA clones. Human LF (hLF) consist of a polypeptide chain of 692 amino acids. The amino terminal region of hLF contains two clusters of basic residues, RRRR (SEQ ID NO:1) (residues 2-5) and RNMRKVR (SEQ ID NO:2) (residues 25-31). The LF polypeptide is folded into two globular lobes, each of which contains an iron-binding cleft. The high affinity of LF for iron confers to the protein certain antibacterial properties and, in addition, may play a role in the absorption of dietary iron by the small intestine.
Some of the biological activities of LF do not arise from the binding of iron but from its capacity to bind to other molecules. Direct intermolecular interactions between hLF and human lysozyme (hLZ) may explain the synergy between the antibacterial action of these two proteins. Interaction of hLF with bacterial outer membrane components such as lipopolysaccharide (LPS) and porins presumably plays an important role in the antimicrobial activity of hLF. Binding of hLF to the lipid A portion of LPS inhibits the LPS priming of neutrophils for enhanced fMLP-triggered superoxide release. Interaction of LF with heparin may account for the neutralization of the anticoagulant activity of heparin.
Some biological activities of LF arise from interactions between LF and cells via membrane bound receptors. For example, LF binding to specific receptors on monocytes, macrophages and activated lymphocytes results in inhibition of cytokine production. Cells that exhibit specific binding to hLF include liver cells, intestinal cells, mammary gland epithelial cells, monocytic cell lines, activated lymphocytes, and platelets.